Remedies for glaucoma comprising bunazosin and prostaglandins

ABSTRACT

The object of the present invention is to find utility of a combination of bunazosin, having a new action mechanism, and prostaglandins as a therapeutic agent of glaucoma. The invention relates to a therapeutic agent of glaucoma, comprising bunazosin or a salt thereof and prostaglandins in combination, where bunazosin or a salt thereof and prostaglandins mutually supplement and/or enhance each action, and where bunazosin and prostaglandin may be formulated in a single preparation to be administered or may be separately administered in combination.

TECHNICAL FIELD

The present invention relates to a therapeutic agent of glaucoma, thetherapeutic agent comprising bunazosin or a salt thereof andprostaglandins in combination.

BACKGROUND OF THE INVENTION

Glaucoma is an intractable ocular disease with a risk of blindness,involving the increase of intraocular pressure due to various factors.Studies have been done about various treating methods therefor. Themethod for lowering intraocular pressure includes three approaches,namely pharmacotherapy, laser therapy and surgery. For thepharmacotherapy, drugs such as β-blockers, prostaglandin-related drugs,carbonic anhydrase inhibitors, cholinergic agents, andepinephrine-related drugs have been used.

Lately, bunazosin hydrochloride, an α1 blocker, was developed as a drugbased on a new action mechanism. Bunazosin hydrochloride is a selectiveblocker of sympathetic nerve α1 receptor and promotes the uveoscleraloutflow to thereby lower intraocular pressure (Folia OphthalmologicaJaponica, 46, 1066-1070, 1995).

As a combination of al blocker and another therapeutic agent ofglaucoma, Japanese Patent Laid-Open Publication (hereinafter referred toas JP-A) 2001-33551 describes a therapeutic agent of glaucoma comprisingan al blocker and an angiotensin II antagonist.

Meanwhile, Japanese Patent No. 2726672 states a combination of anadrenergic receptor blocker and prostaglandins, as a therapeutic agentof glaucoma comprising a combination of prostaglandins and anothertherapeutic agent. However, this Japanese patent has no descriptionabout the effect of a blockers because β blockers in this patent aremainly adrenergic blockers. In particular, this Japanese patent does noteven suggest the effect of al blocker.

As described above, no report has been issued about the effect ontreating glaucoma by a combination of an al blocker and prostaglandins.In particular, studies about bunazosin, an al blocker having a novelaction mechanism, in combination with prostaglandins have never beendone.

Accordingly, it has been a very interesting subject matter to findutility of a combination of bunazosin having a new action mechanism andprostaglandins as a therapeutic agent of glaucoma.

DISCLOSURE OF THE INVENTION

The present inventors made intensive studies about the possibility ofthe development of a therapeutic agent of glaucoma by combiningbunazosin with prostaglandins. Consequently, the inventors found thatthe combination thereof enhanced the action of lowering intraocularpressure, thereby completing the present invention. The detailed testmethod and the results thereof are described below in the section ofPharmacological Test. Bunazosin in combination with prostaglandinsexhibited a remarkable action of lowering intraocular pressure.Additionally, the therapeutic agent of glaucoma in accordance with thepresent invention can be used preferably not only for the treatment ofglaucoma but also for the prevention thereof.

The present invention relates to a therapeutic agent of glaucomacomprising bunazosin or a salt thereof and prostaglandins incombination. These drugs mutually supplement and/or enhance theiractions.

For the treatment of glaucoma, bunazosin and prostaglandins may beformulated in a single preparation to be administered. In other words,these drugs may be administered in mixture. Alternatively, each drug maybe in a separate preparation and these drugs may be administered incombination.

Bunazosin can be in the form of its salt. Examples of the salts includesalts thereof with inorganic acids such as hydrochloric acid and nitricacid. In particular, the hydrochloride salt is preferable.

Since the present invention is characterized by treating glaucoma withbunazosin and prostaglandins in combination, any prostaglandins havingthe action of lowering intraocular pressure and utility in treatingglaucoma may be used, with no specific limitation. Prostaglandins havingthe action of lowering intraocular pressure are exemplified byprostaglandins described in JP-A-Sho59-1418 (natural prostaglandins,particularly prostaglandin F2α), prostaglandins such as latanoprost asdescribed in Published Japanese Translation of PCT No. 3-501025,prostaglandins such as isopropyl unoprostone as described inJP-A-Hei2-108, prostaglandins such as bimatoprost as described inPublished Japanese Translation of PCT No. 8-501310, and prostaglandinssuch as travoprost as described in JP-A-Hei10-182465. In particular,latanoprost, isopropyl unoprostone, bimatoprost or travoprost, which hasalready been on the market as a therapeutic agent of glaucoma, ispreferably used. It is needless to say that these prostaglandins may bein salt forms or ester forms thereof.

According to the embodiment of the invention, the formulation can beeither one formulation containing bunazosin and prostaglandins inmixture or two separate formulations containing each component. Not anyspecific technique is needed for the preparation of these formulations.They are prepared by widely used methods. Preferably, these formulationsare topically administered to eyes. The dosage forms are exemplified byeye drops and eye ointments.

The separate formulations containing bunazosin and prostaglandinsrespectively can be prepared according to known methods. They areexemplified by the formulation disclosed in Japanese Patent PublicationNo. 2610619, the formulation disclosed in Japanese Examined PatentPublication Hei 7-23302, and commercially available formulations. Theformulation of prostaglandins can be prepared with reference to thedescriptions of the above-mentioned Japanese patent laid-openpublications. Commercially available formulations of latanoprost,isopropyl unoprostone and the like as glaucoma-treating agents can beused.

The formulation containing bunazosin and prostaglandins in mixture canbe also prepared according to known methods. The eye drops can beprepared, using isotonic agents such as sodium chloride and concentratedglycerin; buffers such as sodium phosphate buffer and sodium acetatebuffer; surfactants such as polyoxyethylene sorbitan monooleate,stearate polyoxyl 40, and polyoxyethylene hardened castor oil;stabilizers such as sodium citrate and sodium edetate; and preservativessuch as benzalkonium chloride and paraben, as needed. The pH should bewithin an ophthalmologically acceptable range and is preferably within arange of pH 4 to pH 8. For reference, a formulation example thereof isdescribed below in the section of Example. However, the formulationexample never limits the scope of the invention.

The doses of bunazosin and prostaglandins can be determined depending onthe symptom and age of patients, the dosage form, the administrationroute and the like. In case of an administration through eye drops, forexample, bunazosin is administered generally within 2 to 40 μg dailyfrom once to several times a day. The dose of prostaglandins variesdepending on the prostaglandin type. The dose can be determined on thebasis of the actual dose range for treatment and is raised or lowereddepending on the symptom of patients and the like. The daily dose iswithin a range of 1 to 1,000 μg, which is administered from once toseveral times a day. More specifically, isopropyl unoprostone andlatanoprost are generally administered at a daily dose of 30 to 300 μgand a daily dose of 1 to 5 μg, respectively. Depending on the symptom ofpatients and the like, the doses are varied. Based on similar standards,the doses of other prostaglandins can be determined. These doses arealso applicable to the administration of bunazosin and prostaglandins incombination. In case that bunazosin and prostaglandins are to beadministrated in one formulation, the formulation should be prepared byselecting the mixing ratio of two drugs appropriately so that theirdaily doses might not excess each dose of the separate drugs. The mixedformulation is administered from once to several times daily.

A formulation example and a pharmacological test are shown in thefollowing Example. The Example is for better understanding of theinvention but never limits the scope of the invention.

BEST MODE FOR CARRYING OUT THE INVENTION

[Formulation Example]

A general formulation example of eye drops containing bunazosin andprostaglandins in mixture in accordance with the invention is describedbelow. Eye drops (in 100 mL) Bunazosin hydrochloride  0.01 g Latanoprost0.005 g Boric acid  0.5 g Concentrated glycerin  2.0 g Benzalkoniumchloride  0.01 g Dilute hydrochloric acid q.s. Distilled water q.s.[Pharmacological Test]

So as to study the utility of bunazosin in combination withprostaglandin, bunazosin and prostaglandin were administered incombination to cynomolgus monkeys (Macaca fascicularis), examining theeffect on intraocular pressure. Latanoprost was used as prostaglandin.

(Test Compound Solution)

For bunazosin administration, Detantol (trade mark) ophthalmic solution,which contains bunazosin hydrochloride at 0.01%, was used. Forlatanoprost administration, Xalatan (trade mark) ophthalmic solution,which contains latanoprost at 0.005%, was used.

(Dosing Groups)

Cynomolgus monkeys were divided into four groups, a group to be dosedwith a vehicle (vehicle group), a group to be dosed with bunazosin(bunazosin group), a group to be dosed with latanoprost (latanoprostgroup) and a group to be dosed with bunazosin and latanoprost[(bunazosin+latanoprost) group].

(Administration Method and Measurement Method)

-   -   1. For topical anesthesia, a drop of 0.4% oxybuprocain        hydrochloride ophthalmic solution was instilled into a single        eye of each normal cynomolgus monkey. Then, intraocular pressure        was measured before drug administration.    -   2. Then, each test compound solution was administered. To the        vehicle group, 20 μl of the vehicle solution was instilled. To        the bunazosin group, 20 μl of Detantol ophthalmic solution was        instilled. To the latanoprost group, 20 μl of Xalatan ophthalmic        solution was instilled . To the (bunazosin+latanoprost) group,        20 μl of Detantol ophthalmic solution was instilled and 5        minutes later 20 μl of Xalatan ophthalmic solugion was        instilled.    -   3. 2, 4 and 6 hours after the administration of these test        compound solutions, one drop of 0.4% oxybuprocain hydrochloride        eye drops was instilled for topical anesthesia, and the        intraocular pressure was measured. The maximum reduction of        intraocular pressure in each group was determined by the        following formula. (Maximum reduction of intraocular        pressure)=(intraocular pressure at the time when the intraocular        pressure was decreased mostly)−(intraocular pressure before drug        administration)        (Results and Discussion)

The experimental results are shown in Table 1. TABLE 1 Maximum reductionof intraocular pressure (mmHg) Vehicle group 0.9 Bunazosin group 1.9Latanoprost group 2.6 Bunazosin + latanoprost group 3.0

As shown in Table 1, the intraocular pressure in the group dosed withbunazosin and latanoprost was lowered more than those in the bunazosingroup and the latanoprost group. Those described above show that thecombination of bunazosin and prostaglandins can bring about a remarkablereduction of intraocular pressure.

Industrial Applicability

The administration of bunazosin and prostaglandins in combinationenhanced the intraocular pressure-lowering effect of each drug. Thus,the pharmaceutical composition of the invention is useful as atherapeutic agent of glaucoma.

1. A therapeutic agent of glaucoma, comprising bunazosin or a saltthereof and a prostaglandin in combination.
 2. A therapeutic agent ofglaucoma, comprising bunazosin or a salt thereof and a prostaglandin incombination, where these drugs mutually supplement and/or enhance theactions thereof.
 3. A therapeutic agent of glaucoma according to claim 1or 2, where the prostaglandin is latanoprost.
 4. A method for treatingglaucoma, comprising administration to a patient with a therapeuticallyeffective amount of bunazosin or a salt thereof and a prostaglandin incombination.
 5. A method for treating glaucoma according to claim 4,where the prostaglandin is latanoprost.